2-Heterosubstituted 3-aryl-4H-1-benzopyran-4-ones as novel therapeutics in breast cancer
View Patent ↗The present invention provides 2-heterosubstituted 3-aryl-4H-benzopyran-4-one compounds for the treatment of cancers, namely breast cancer. This invention further provides a method of synthesis of 2-(alkylthio)isoflavones that can be carried out at ambient conditions. This invention further provides a method of synthesis of the 2-heterosubstituted 3-aryl-4H-benzopyran-4-one from a 2-(alkylthio)isoflavone. The invention further provides methods of using the 2-heterosubstituted 3-aryl-4H-benzopyran-4-one compounds for the treatment of breast cancer in mammals.
1. A compound of formula A:
wherein
X is selected from the group consisting of O, N, S, SO, and SO 2 ;
R 1 and R 2 can be the same or different and are selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 , OCH 2 CH 5 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , NO 2 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , OCOCH3, OCOC(CH 3 ) 3 , and OCOCH 2 COOH;
R 3 is
2. A compound of formula A:
wherein
X is selected from S, N, and O;
R 1 and R 2 can be the same or different and are selected from the group consisting of H, OH, OCH 3 , OCH 2 H 3 , CCH 2 C 6 H 5 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , NO 2 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , OCOCH 3 , OCOC(CH 3 ) 3 , and OCOCH 2 COOH; and
R 3 is 2-(1-piperidinyl)ethoxy.
3. The compound of claim 2 , wherein X is S, R 1 is OH, R 2 is OCH 3 , and R 3 is 2-(1-piperidinyl)ethoxy.
4. The compound of claim 2 wherein
X is selected from S and O;
R 1 is selected from OH, OCH 3 , and OC 6 H 5 ;
R 2 is selected from H, OH, CH 3 , and OCH 3 ; and
R 3 is 2-(1-piperidinyl)ethoxy.
5. The compound of claim 2 , wherein X is S, R 1 is OC 6 H 5 , R 2 is OCH 3 , and R 3 is 2-(1-piperidinyl)ethoxy.
6. The compound of claim 2 , wherein X is O, R 1 is OC 6 H 5 , R 2 is OCH 3 , and R 3 is 2-(1-piperidinyl)ethoxy.
7. The compound of claim 2 , wherein X is O, R 1 is OH, R 2 is OCH 3 , and R 3 is 2-(1-piperidinyl)ethoxy.
8. A one-pot method for preparing a 2-(alkylthio)isoflavone comprising the steps of:
a. providing a mixture of a deoxybenzoin, carbon disulfide, alkyl halide, and tetrabutylammonium hydrogensulfate;
b. adding aqueous sodium hydroxide to the mixture while stirring;
c. reacting the mixture until the 2-(alkylthio)isoflavone is formed.
9. The method of claim 8 wherein the mixture is allowed to stir for about 3 to about 7 hours after the addition of the sodium hydroxide.
10. The method of claim 8 further comprising the step of separating the 2-(alkylthio)isoflavone from the reaction mixture.
11. The method of claim 10 further comprising the step of purifying the 2-(alkylthio)isoflavone compound.
12. A method of prepararing a 2-heterosubstituted 3-aryl-4H-benzopyran-4-one compound comprising the steps of:
a. selecting a 2-(alkylthio)isoflavone;
b. optionally protecting potentially reactive groups on the 2-(alkylthio)isoflavone;
c. oxidizing the alkylthio group to a alkylsyfonyl group; and
d. substituting the alkylsulfonyl group with a heteroalkyl or heteroaryl group to form the 2-heterosubstituted 3-aryl-4H-benzopyran-4-one compound.
13. The method of claim 12 wherein the oxidation step is carried out using mCPBA in a polar aprotic solvent under reflux conditions.
14. The method of claim 12 wherein the polar aprotic solvent is CH 2 Cl 2 .
15. The method of claim 12 wherein alkylsulfonyl group is substituted with a thioaryl group.
16. The method of claim 15 further comprising the step of substituting the thioaryl group with an ethylpiperidinyl group to form a 4-[2-(1-piperidinyl)ethoxy]thiophenyl group at the 2-position of the 2-heterosubstituted 3-aryl-4H-benzopyran-4-one compound.
17. The method of claim 16 further comprising the step of deprotecting the 2-heterosubstituted 3-aryl-4H-benzopyran-4-one.
18. The method of claim 12 further comprising the step of deprotecting the 2-heterosubstituted 3-aryl-4H-benzopyran-4-one.
19. A method for treating, inhibiting, or delaying the onset of a breast cancer in a subject in need of such treatment; the method comprising administering a therapeutically effective amount of compound A:
wherein
X is selected from the group consisting of O, N, S, SO, and SO 2 ;
R 1 and R 2 can be the same or different and are selected from the group consisting of H, OH, OCH 3 , OCH 2 CH 3 , OCH 2 C 6 H 5 , NH 2 , NHCH 3 , N(CH 3 ) 2 , CN, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , C(CH 3 ) 3 , NO 2 , F, Cl, Br, CF 3 , SH, SCH 3 , SCH 2 CH 3 , OCOCH3, OCOC(CH 3 ) 3 , and OCOCH 2 COOH; and
R 3 is 2-(1-piperidinyl)ethoxy
to the subject in need of such treatment.
20. The method of claim 19 wherein the cancer is hormone-dependent breast cancer.